CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases
2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 42, 39666-39672 p.Article in journal (Refereed) Published
The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation. More recently, a novel pathway has been identified whereby Cbl promotes internalization of EGF receptor via a CIN85/endophilin pathway that is functionally separable from the ubiquitin ligase activity of Cbl (1). Here we show that Cbl-b, but not Cbl-3, utilize the same mechanism to down-regulate multiple RTKs. CIN85 was shown to bind to the minimal binding domain identified in the carboxyl terminus of Cbl-b. Ligand-induced phosphorylation of Cbl-b further increased their interactions and led to a rapid and sustained recruitment of CIN85 in the complex with EGF or PDGF receptors. Inhibition of binding between CIN85 and Cbl-b was sufficient to impair Cbl-b-mediated internalization of EGF receptors, while being dispensable for Cbl-b-directed polyubiquitination of EGF receptors. Moreover, CIN85 and Cbl/Cbl-b were constitutively associated with activated PDGF, EGF, or c-Kit receptors in several tumor cell lines. Our data reveal a common pathway utilized by Cbl and Cbl-b that may have an important and redundant function in negative regulation of ligand-activated as well as oncogenically activated RTKs in vivo.
Place, publisher, year, edition, pages
2002. Vol. 277, no 42, 39666-39672 p.
3T3 Cells, Adaptor Proteins; Signal Transducing, Animals, CHO Cells, Carrier Proteins/*metabolism, Cell Line, Cell Line; Transformed, Cloning; Molecular, Cricetinae, Down-Regulation, Endocytosis, Epidermal Growth Factor/metabolism, Hela Cells, Humans, Ligands, Mice, Microscopy; Fluorescence, Models; Biological, Phosphoproteins/*metabolism, Phosphorylation, Platelet-Derived Growth Factor/metabolism, Precipitin Tests, Protein Binding, Protein Structure; Tertiary, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-kit/metabolism, Receptor Protein-Tyrosine Kinases/*metabolism, Time Factors, Transfection, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-90465DOI: 10.1074/jbc.M205535200PubMedID: 12177062OAI: oai:DiVA.org:uu-90465DiVA: diva2:162828